Developments in hybridoma technology have opened new avenues for the treatment of cancer and other disease states. For purposes of in vivo therapy, monoclonal antibodies having specificity for an in vivo target, such as tumor tissue, have been administered alone with direct cytotoxic effect. Alternatively, monoclonal antibody conjugates comprising cytotoxic agents, such as drugs, toxins or radioisotopes covalently bound to monoclonal antibodies have been administered to mediate the selective delivery of such agents to a tumor target. However, reported trials of monoclonal antibodies administered alone have yielded inconsistent results. While transient anti-tumor effects have been observed in several studies, desirable complete remissions have generally not resulted. In vivo trials with monoclonal antibody conjugates of drugs, toxins or radioisotopes are still in the early developmental stages.
Anthracycline compounds and their derivatives have generally proven useful as anti-tumor agents in the treatment of cancer, including lymphomas, leukemias, sarcomas and cancers of the breast and lung. Among the anthracyclines most useful as anti-tumor agents are doxorubicin and daunorubicin. Doxorubicin, one of the most commonly used chemotherapeutic agents, displays activity against a wide range of human neoplasms. Doxorubicin is effective in the treatment of acute leukemias and malignant lymphomas and has been administered as a single agent, or in combination with other agents to treat, for example, chronic lymphocytic leukemia ("CLL") or cutaneous T-cell lymphoma ("CTCL"). Additionally, doxorubicin is a valuable component of various regimens of chemotherapy for carcinomas of the breast and lung, and is beneficial in the treatment of a wide range of sarcomas. By comparison, daunorubicin is very useful in the treatment of acute lymphocytic and acute granulocytic leukemias.
Antibody conjugates comprising anthracycline agents covalently attached to antibodies have been prepared using a variety of techniques. One such technique employs dextran to provide covalent linkages between the antibody and the anthracycline agent, e.g. doxorubicin. It has been extremely difficult, however, to prepare effective conjugates comprising anthracyclines and antibodies. Significantly, the size of such conjugates results in rapid clearance by the reticuloendothelial system. Additional limitations inherent in the use of such conjugates include the need for modification of the anthracycline agent prior to covalent attachment to the antibody, usually resulting in decreased potency, and the need for metabolic cleavage of the agent from the antibody to produce the desired cytotoxic effect at the in vivo target. Further, conjugation may impair the immunoreactivity and alter the biodistribution of the antibody, usually resulting in decreased concentration at the target tissue, and may increase immunogenicity.
The problems enumerated in the foregoing are not intended to be exhaustive, but are among many which tend to limit the clinical value of antibody conjugates of anthracyclines as anti-tumor agents. Accordingly, while the selective delivery of anthracycline agents to an in vivo target may be accomplished, there continues to exist a need to enhance the cytotoxic efficacy of anthracycline at the target tissue.